Method of making 5-anilino uracils



United States Patent ABSTRACT OF THE DISCLOSURE This invention isdirected to. a method of preparing compounds of the formula whichcomprises the reaction between S-aminouracil or a S-N-alkylaminouracilwith the appropriate aniline or N- R-aniline in the presence of mineralacid. The compounds produced by this invention are useful asintermediates and may be converted to compounds which act asantimalarials and as bactericides.

III-phenyl R This invention relates to the preparation of pyrimidines,and in particular to the preparation of 2,4-dihydroxy--anilinopyrirnidines (5 anilinouracils) and derivatives thereof.

In British patent specification No. 971,307 there is disclosed thepreparation of S-anilinouracils from S-bromouracil and the appropriateanilines. The reaction is carried out by refluxing the reactants in ahigh-boiling hydroxylic solvent such as ethylene glycol. This method isnot entire ly satisfactory since the yields of the S-anilinouracils arefrequently low.

It has now been found that a S-anilinouracil of Formula I may beobtained in good or excellent yield by heating a S-aminouracil or aS-N-alkylaminouracil with an aniline or an N-R-aniline in the presenceof about one equivalent of a mineral acid.

In Formula I N NR IR HNR l l (excess) HO N Q EX L r q HO I wherein R, Rand R are members of the class consisting of lower alkyl and hydrogenandNR R may also be a cyclic group such as piperidino, pyrrolidino ormorpholino, and the phenyl group may bear one or more substituents, forexample halogen atom, alkyl, nitro and alkoxy groups. When it is desiredto obtain an N-alkylanilinouracil of Formula I, the appropriateN-alkylaniline reactant should be chosen. When a S-N-alkylaminouracil isused as a reactant, the alkyl group is removed in the course of thereaction and the end product does not bear the said alkyl group.

3,419,558 Patented Dec. 31, 1968 In preparing a S-anilinouracil ofFormula I, it is convenient to use considerable excess of the aniline asa solvent, preferably at least two equivalents. The mineral acid may beintroduced into the reaction mixture either as the free acid or combinedwith one of the amine reactants. For example S-aminouracil hydrochloridemay be added to the appropriate aniline, or S-aminouracil together withone equivalent of aniline hydrochloride may be mixed with the remainderof the aniline in the form of the base. Other strong acids such assulphuric acid, hydrobromic acid or phosphoric acid may be used in placeof hydrochloric acid.

The reaction is preferably carried out at a temperature of about 200 C.When the reactants are aniline or a toluidine, this temperature may beattained by refluxing the reaction mixture. When other higher boilingamines are used, the reaction mixture is heated in an oil bath or ametal bath at about 200 to 220 C. When the aniline is a solid it isheated to its melting point if it is above 200 C.

These S-anilinouracils can be converted into derivatives, for example bychlorination, amination of chloro compounds with ammonia, or bythiation. Thus, 2,4-dihydroxy- S-anlinopyrimidine (S-anilinouracil) isconverted into 2,4- dichloro-S-anilinopyrimidine by reaction withphosphoryl chloride, and this is converted into2,4-diamino-5-anilinopyrimidine by heating with alcoholic ammonia. Thesetransformations are fully described in British patent specification No.971,307.

This invention therefore provides a method for the preparation of aS-anilinouracil of the formula wherein X and Y are each a hydroxy group,R is a hydrogen atom or a lower alkyl group preferably containing 1 to 5carbon atoms and the phenyl group may bear isubstituents, for examplehalogen atoms, alkyl, nitro and alkoxy groups, which comprises thereaction between a 5- aminouracil or a S-N-alkylaminouracil with theappropriate aniline or N-R-aniline in the presence of a mineral acid,and the further optional step of transforming by chlorination, aminationor thiation a product prepared as above into a derivative thereofwherein each of X and Y is an amino group, a chlorine atom or a mercaptogroup.

' The 2,4-diamino derivatives of the compounds of Formula I, for whichthe compounds of Formula I are intermediates are useful as antimalarialdrugs and as bactericides. The 2,4-dihydroxy compounds (for example theS-anilinouracil and 5-m-toluidinouracil derivatives) have the ability tosuppress immune response in experimental animals, and are therefore ofpotential value in connection with surgical transplantation.

The following examples illustrate the invention. Temperatures are indegrees Celsius. Generally, the S-anilinouracils melt at rather hightemperatures, probably with decomposition. As a result principalreliance for characterisation is placed on the ultra-violet absorptionspectra rather than on the melting point.

BIT-phenyl R Example 1.--5-anilinouracil Aniline (10 ml.) andS-aminouracil hydrochloride (1.5 g., 8 mmoles) were heated underrefluxed for 4 /2 hours. The reaction mixture was cooled and poured intowater. The aqueous solution was washed with ether and placed in arefrigerator overnight. The precipitated solid was col- 3 lected, washedwith acetone and slurried with concentrated hydrochloric acid for 15minutes. It was again filtered, washed with water and acetone and dried.The product weighed 1.5 g.

Example 2.-anilinouracil This reaction was carried out in the manner ofExample 1 except that S-N-n-butylaminouracil hydrochloride was employedin place of S-aminouracil hydrochloride. The material was identical withthat obtained from Example 1.

Example 3.5-anilinouracil from S-piperidino uracil Two g. (0.01 mole) of5-piperidino uracil, 2.6 g. (0.02 mole) of aniline hydrochloride and 3ml. of aniline were heated to reflux for 4.5 hours. Solid was presentthroughout this period. After standing over-night the reaction mixturewas diluted with water and acetone and filtered. The precipitate waswashed successively with water and acetone.

The product which was not quite colorless weighed 2 grams crude. It wasrecrystallized from Methyl Cellosolve and was then analytically pure.

Using the same procedure S-amino uracil was reacted with p-bromoanilineand with O-nitroaniline 5-p-bromoanilino uracil was obtained in 81%yield and 5 o-nitroanilinouracil in 31% yield.

In Table 1 below are shown the results of the preparation of furthercompounds of Formula I by the method of the invention in the mannerdescribed in Example 1. Also shown in the Table are the yields obtained,and the physical properties of the products including those of theproduct of Examples 1 and 2.

and nitro, which comprises heating at a temperature of around 200 C. acompound of the formula with an excess of an aniline HNR' phenyl and atleast about one equivalent of a strong mineral acid, wherein R, R and Rare members from the class consisting of I NR R hydrogen and loweralkyl, and NR R may also be piperidino, pyrrolidino or morpholino.

Percent Ultra violet absorption spectra C m ound iF rmula I Per en ieldbM.P. C.

0 p o o yigid t 111 mm 2': pH A max. max. 6 .10- min. min. e .10-

1' 4 d 324 1 382 17.3 287 3.3 5 p nitroanilmou acll 80 3 8 6. 6 272 6- 0398 17.9 320 4. 0 E-p-anisidinouracil 92 83-91 I 305-310 1 249 11. 2 2268. 4

312 (SL) 3. 5 13 12. 4 297 (SL) 5.3 6-p-chlorani1inouracil 73 46-68 1300 1 48 9. 95 13 242 12.1 p 295 (SL) 4.8 E-N-see. amylanilinouracil 7046 303-307 1 277 8. 0

13 234 12.3 290 (SL) 6.0 E-aniiinouracil 93 70-85 1 300 1 240 11.6 13235 11.6 287 (SL) 6. 2 fi-m-chloroanilinouracil 92 25-30 1 307 1 244 12.4 13 245 10. 8 288 6. 5 E-N-methylanilinouracil 69 24-45 264-265 1 24517. 1 325 (SL) 1.9 13 251 14. 6 228 9. 3 285 8.0 280 7. 8o-o-chloroanilinouracil 7-12 1 309-312 1 240 13. 0 227 11. 1 13 239 12.2 230 11.2 289 7. 5 271 6.8 fi-o-toluidinouracil 94 42-59 1 295-297 1240 13.0 227 11. 1 13 239 12.2 230 11.2 289 7. 5 271 6. 3

1 Decomposition.

What I claim is: References Cited 1. The method of preparmg a compoundof the formula FOREIGN PATENTS 971,307 9/1964 Great Blltaln. OH

X OTHER REFERENCES N N@ Krumbiegel et 211.: Z. Physlk. Chem. (Lelpzig),vol. L i t. 227 (3/4 1964, pp. 179-86. 5 HO NICHOLAS s. RIZZO, PrimaryExaminer.

wherein R is selected from the class consisting of hydro- R. J.GALLAGHER, Assistant Examiner.

U.S. Cl. X.R.

gen and lower alkyl and X is selected from the class l67-33;65, 78

consisting of lower alkyl, lower alkoxy, halogen, hydrogen

